Indications

The first therapy to work against HIV was the nucleoside reverse transcriptase inhibitor zidovudine. The FDA approved this in 1987. By 1996, research showed the advantages of combining medicines to treat HIV. Using HIV medicines for treatment is called antiretroviral therapy (ART). This form of treatment is recommended for all patients with HIV by the Department of Health and Human Services (DHHS) and the World Health Organization (WHO). This daily treatment of multiple HIV medications is an HIV regimen. A typical, initial HIV regimen includes three HIV medications from a minimum of two drug classes. Although this treatment is not curative, it can provide longer lives for patients and reduce HIV transmission. This reduction of transmission has become a popular use of antiretroviral therapy for individuals who are HIV-positive and are with an HIV-negative partner. The successes of antiretroviral therapy have reduced HIV to a chronic condition in many parts of the world as progression to AIDS has become rare. Studies have found that 3-drug therapy has led to a 60% to 80% decline in rates of AIDs, hospitalization, and death. By 2030 the CDC plans to implement a 90-90-90 plan (90% HIV diagnosed, 90% on therapy, and 90% suppressed).

The goal of HIV medicines is to prevent HIV from multiplying. There are six classes of drugs used in antiretroviral therapy. These drugs generally fall into classes according to the phase of the HIV life cycle inhibited by them. More common combinations include two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), a protease inhibitor (PI), or integrase inhibitor (II). The drugs are listed below according to their class and generic names.

People who are exposed to HIV-positive infectious bodily fluids either by skin puncture, damaged skin, or direct mucous membrane contact are at risk for transmission and should start antiretroviral therapy as soon as possible. The United States Public Health Service guidelines recommend starting prophylactics up to 72 hours post-exposure. The recommended regimen is emtricitabine plus tenofovir plus raltegravir for four weeks. Those who get exposed to HIV should have follow-up HIV testing at 6, 12, and 24 weeks. If the test results are negative at 24 weeks, they are considered uninfectious.[1]

A recent HIV Infection is one that occurs up to 6 months after infection. An HIV regimen often varies based on potential drug interactions with the patient's current medications and the adverse effects experienced.

Patients who are pregnant should begin treatment immediately to prevent mother-to-child transmission of HIV and protect the health of the woman.[2][3][4][5][6]

The FDA does not approve investigational HIV drugs. Investigational drugs include those used to treat or prevent HIV and vaccines to treat or prevent HIV. These drugs are only available in clinical trials. No vaccines exist yet; however, researchers are studying this possibility.[7]

Mechanism of Action

NRTIs

Compete with natural deoxynucleotides for incorporation into a growing viral DNA chain. However, NRTIs lack a 3'-hydroxyl group on the deoxyribose moiety. This difference results in incorporation of an NRTI, and the next incoming deoxynucleotide cannot form the following 5', 3' phosphodiester bond needed to extend the DNA chain. The result is a chain termination in DNA synthesis.

NNRTIs

Block reverse transcriptase (RT) by directly binding to the enzyme. Though NNRTIs do not get incorporated into the viral DNA, they inhibit movement of protein domains of RT that are essential to carry out the DNA synthesis.

Protease Inhibitors

Bind HIV-1 protease and block proteolytic cleavage of protein precursors that are necessary for the production of viral particles.

Fusion Inhibitors

Disrupt binding, fusion, and entry of HIV virions into a human cell. Enfuvirtide binds to gp41 and disrupts membrane attachment.

CCR5 Antagonist

Maraviroc blocks the CCCR receptor on the T-Cell to prevent viral attachment.

Integrase Inhibitors

Block the action of integrase, preventing the viral genome from inserting itself into the DNA of a host cell.

Post-Attachment Inhibitors

This class is a monoclonal antibody that binds CD4 inhibiting viral entry into the cell.

Administration

The standard of care in an HIV regimen is to prevent HIV mutation. As a patient will take these medications orally, there are now several options that combine three to four drugs into one pill for once-daily administration. This dosing increases both adherence and long-term effectiveness. Ibalizumab is an exception as it is an injectable agent.[8]

Patients are tested and educated to take all of their medications correctly to reduce resistance and cross-resistance to similar drugs to those they are taking. Medication adherence has been found to be difficult due to adverse effects following an HIV regimen. Common barriers to adherence include trouble swallowing pills, busy schedule (shift work), unstable living/housing situations, alcohol and drug use, fear of disclosing HIV status, and lack of insurance. Before starting an HIV regimen, strategies such as 7-day pillboxes and/or phone applications and alarms should be in place. Patients must have stable mental health and not be taking illicit drugs to have better adherence.[9][10]

Zidovudine: Patients who have had potentially life-threatening allergic reactions (e.g., anaphylaxis, Stevens-Johnson syndrome) to any of the components of the formulations.

Efavirenz: Patients with clinically significant hypersensitivity, for example, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the ingredients of this product. Coadministration of efavirenz with elbasvir and grazoprevir is contraindicated.

Etravirine: Hypersensitivity

Nevirapine: In patients with moderate or severe (Child-Pugh Class B or C, respectively) hepatic impairment or for use as occupational and non-occupational post-exposure prophylaxis (PEP) regimens. Women with CD4 greater than 250 or men with CD4 greater than 400 due to an increased probability of hypersensitivity reaction.

Atazanavir: In patients with previously demonstrated clinically significant hypersensitivity, for example, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions, to any of the ingredients of formulations. When co-administered with medications that are highly dependent on CYP3A or UGT1A1 for clearance, and for patients in which elevated plasma concentrations of the interacting drugs are associated with serious and life-threatening events. When co-administered with drugs that strongly induce CYP3A4 it may lead to lower exposure and loss of efficacy of formulations.

Darunavir: Co-administration of formulations is contraindicated with medications that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events.

Fosamprenavir: In patients with previously demonstrated clinically significant hypersensitivity, for example, Stevens-Johnson syndrome, to any of the components of this product or amprenavir. When co-administered with medications that are highly dependent on cytochrome P450 3A4 (CYP3A4) for clearance and for which elevated plasma concentrations are associated with serious and life-threatening events.

Ritonavir: Contraindicated in patients with known hypersensitivity, for example, toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome, to ritonavir or any of its ingredients. Ritonavir is contraindicated with medications that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and life-threatening reactions. It is also contraindicated with medications that are potent CYP3A inducers, where significantly reduced lopinavir plasma concentrations may correlate with the potential for loss of virologic response and possible resistance and cross-resistance.[15]

Saquinavir: Contraindicated in those with congenital long QT syndrome, those with refractory hypokalemia or hypomagnesemia, and combination with drugs that both increase saquinavir plasma concentrations and prolong the QT interval. Is also contraindicated in people with complete atrioventricular (AV) block without implanted pacemakers, or in patients who are at high risk of complete AV block. Contraindicated in patients with clinically significant hypersensitivity (e.g., anaphylactic reaction, Stevens-Johnson syndrome) to saquinavir, saquinavir mesylate, or any of its ingredients. Contraindicated in patients with severe hepatic impairment. Is also contraindicated with drugs that are CYP3A substrates for which increased plasma levels may result in serious or life-threatening reactions.

Tipranavir: Contraindicated in moderate to severe hepatic impairment and co-administration with drugs that are highly dependent on CYP 3A for clearance or are potent CYP 3A inducers. Increased risk of intracranial bleeding.

Enfuvirtide: Known hypersensitivity to enfuvirtide or any of its components.

Maraviroc: This drug is contraindicated in patients with severe renal impairment or ESRD (CrCl less than 30 mL per minute) who are concomitantly taking potent CYP3A inhibitors or inducers.

Dolutegravir: With previous hypersensitivity reaction to dolutegravir or receiving dofetilide due to the potential for higher dofetilide plasma concentrations and the risk for serious and life-threatening events.

Raltegravir: None

Ibalizumab: None

Cobicistat: The concomitant use of cobicistat with atazanavir or darunavir and is contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect.

Monitoring

Initial Assessment/Start of Antiretroviral Therapy

CD4 Count

HIV viral load

Resistance testing

HLA-B 5701 testing

Tropism testing

Hepatitis B serology

Hepatitis C screening

Complete blood count (CBC) with differential

Basic chemistry

ASL/AST/bilirubin

Fasting lipid profile

Fasting glucose and hemoglobin A1C

Urinalysis

Pregnancy Test

Every 3 to 6 Months

CD4 count for first 2 years of antiretroviral therapy or if viremia develops

HIV viral load

Basic chemistry

ALT/AST/ bilirubin

CBC with differential if on zidovudine

Fasting glucose and hemoglobin A1C if abnormal before

Every 6 Months

CBC with differential

Urinalysis if on (bictegravir, emtricitabine, and tenofovir alafenamide) or (efavirenz, emtricitabine, and tenofovir disoproxil fumarate

Every 12 Months

After two years, if the CD4 count is 300 to 500, then every 12 months; if CD4 is greater than 500, monitoring is optional

Hepatitis B serology may be repeated unless immunized

Hepatitis C screen if the patient is at risk

Fasting lipid profile

Fasting glucose and hemoglobin A1C

Urinalysis

Quantiferon TB test

Treatment Failure/Modification

CD4 count

HIV viral load

Resistance testing

Tropism testing

Hepatitis B serology

Hepatitis C screening

Basic chemistry

ALT/AST/bilirubin

CBC with differential

Fasting lipid profile

Fasting glucose and hemoglobin A1C

Urinalysis

Pregnancy test

Toxicity

Many HIV medicines have adverse effects that may require supportive treatment, monitoring, and adjustment of the HIV regimen.[12]

Enhancing Healthcare Team Outcomes

The management of HIV patients is best done with a multidisciplinary team that also includes the pharmacist and infectious disease nurse. The pharmacist should verify the chosen regimen, check for drug interactions, verify dosing, and assumes a responsibility for patient counseling. Nursing can make an initial assessment on treatment effectiveness and especially patient compliance. Nursing also must participate in patient education, because improer complaince can lead to disastrous therapeutic failure. All members of the healthcare team must press the point of compliance when they have the opportunity, and any concerns about the regimen or compliance must be communicated to the treating physician.

There is overwhelming data showing that HAART can improve survival and reduce the risk of opportunistic infections. Thus, healthcare workers need to understand these medications not only because of their effectiveness but also the potential adverse effects that can occur. When in doubt about HAART, a consultation with an infectious disease expert is recommended.

Only with a complete "all in", collaborative interprofessional team approach can ART have its best chance for therapeutic success while minimizing adverse events. [Level V]

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A patient with HIV/AIDS is being treated with nelfinavir, lamivudine, and zidovudine. His only side effect is fatigue. The viral load is suppressed, but a complete blood count shows WBC 5,000 cells/mm3, Hgb 10.3 g/dL, Hct 30.2%, Plts 132,000 cells/mm3, and MCV 109 fL. Which of the following statements is true?

The fatigue caused by the degree of anemia is unacceptable, so all three drugs must be changed

The medication should be changed, as the present combination has failed

No changes need to be made

B12 and folate supplementation should be started

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A patient with HIV/AIDS has been maintained on nelfinavir plus lamivudine and zidovudine for six months. At four months, there was no detectable viral RNA. He reports a 15-pound weight loss, night sweats, but no fevers. Labs show WBC 3,600 cells/mm3, Hgb 9.6 g/dL, Plts 140,000, and MCV 113 fL. Viral load is 8,000 copies/ml and the CD4+ count has decreased. Which of the following is the appropriate treatment for this patient?

The drugs should be continued as the side effects are not severe and treatment is a success

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A patient with HIV is started on Indinavir (Crixivan), Stavudine (d4T), and Didanosine (ddI). The patient develops severe right flank pain with radiation to the groin. The patient has urgency, dark urine, and hesitance. On exam, the patient is in severe pain, with right upper quadrant tenderness to deep palpation and right costovertebral angle (CVA) tenderness. Which of the following choices is appropriate for the management of this patient?

Urinalysis, electrolytes, BUN, creatinine, and uninfused CT of the abdomen and pelvis

Infused CT and surgical consult for possible appendectomy

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A newborn infant is diagnosed with HIV and started on highly active antiretroviral therapy (HAART). The infant is evaluated, and the mother admits she stopped the medication two months ago because she kept missing doses. Laboratory results show a CD4+ count of 300 cells/mm3 and an HIV viral load of 50,000 copies/mL. Previously the CD4+ count was 700 cells/mm3, and the HIV viral load was 6,000 copies/mL. Which of the following is appropriate for the management of this infant?

The mother should be reprimanded because now the treatment will be more difficult

Further HAART will not be helpful given the low CD4+ count

Stopping the medication was correct; it is better not to take HAART if compliance cannot be assured

Continuing the medication even with questionable compliance would have been preferable

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Beginning antiviral therapy at this point would have no effect on morbidity and mortality

Treatment should be recommended and include a CCR5 antagonist to prevent treatment failure

Treatment should be recommended with two nucleoside reverse transcriptase inhibitors and one protease inhibitor

Treatment should be recommended with one nucleoside reverse transcriptase inhibitor and one integrase inhibitor

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A 35-year-old woman comes to your office to establish primary care. She has not been seen by a doctor in 15 years and says she has been very healthy and endorses no complaints. Family history is only positive for breast cancer in a maternal aunt. On social history she says she is has been married for 3 years and is in a monogamous relationship, they use condoms intermittently, although admits that in the past she had multiple sexual partners. Routine testing reveals positive for HIV-1. Further testing shows a CD4 count of 1075. What should the next step be?

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Use of antiretroviral therapy during pregnancy and adverse birth outcomes among women living with HIV-1 in low and middle-income countries: a systematic review., Saleska JL,Turner AN,Maierhofer C,Clark J,Kwiek JJ,, Journal of acquired immune deficiency syndromes (1999), 2018 May 25 [PubMed]

Mother-to-child transmission of HIV in Australia and other high-income countries: Trends in perinatal exposure, demography and uptake of prevention strategies., O'Donovan K,Emeto TI,, The Australian & New Zealand journal of obstetrics & gynaecology, 2018 May 22 [PubMed]

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